Novel c-16,17 spiro-orthoester steroids and preparation

ABSTRACT

C-16,17 spiro-orthoesters and method of preparation involving reacting a 16,17-dihydroxy steroid with an O-alkyl alkanoic acid lactonium tetrafluoroborate in the presence of a base. The novel spiro-orthoesters are useful anti-inflammatory agents.

United States Patent 1191 Ackrell et al.

[ 1 NOVEL C-16,17 SPlRO-ORTHOESTER STEROIDS AND PREPARATION Syntex Panama Filed: May 14, 1970 App1.No.: 37,292

[73] Assignee: Corporation, Panama,

US. Cl. ..260/239.55 D, 260/999 Int. Cl .L ..C07c 173/00 Field of Search ..Machine Searched Steroids References Cited UN' A1E3A NT 3,338,926 8/1967 Alvarez et a1. .;.260/397.4

[ Feb. 13, 1973 3,546,215 12/1970 Fried ..260/239.55 3,073,743 1/1963 Spero ..l67/65 3,073,817 1/1963 Diassietal. ..260/239.55 3,174,971 3/1965 Krakoweretal ..260/239.55

Primary Examiner-Henry A. French Attorney-Evelyn K. Merker, Gerard A. Blaufarb and Walter H. Dreger the presence of a base. The novel spiro-orthoesters are useful anti-inflammatory agents.

ABSTRACT Claims, No Drawings NOVEL C-l6,l 7 SPlRO-ORTHOESTER STEROIDS AND PREPARATION This invention relates to novel l6,l7-spiroorthoester steroids in the corticoid series and to a novel process for preparing these compounds using an alkyl alkanoic acid lactonium tetrafluoroborate in the presence of a base.

The 16,17-spiro-orthoester corticoid steroids of the present invention can be represented by the following general formulas (A) and (B):

wherein, in each applicable formula,

R is hydrogen, hydroxy, fluoro, chloro, bromo, al-

koxy, phenyloxy, or carboxylic acyloxy of less than 12 carbon atoms; R is hydrogen, fluoro, chloro, bromo, or methyl; R is hydrogen, chloro, fluoro, or bromo; R is oxygen or the group in which R is hydroxy or, (when R is bromo or chloro), bromo, chloro, or fluoro;

each 2 is a carbon-carbon single bond or a carboncarbon double bond; and n is the positive integer l,2,3, or 4. Particularly preferred are those compounds of Formulas (A) and (B) in which R is hydroxy, chloro, or fluoro, R is fluoro, R is chloro, and R is the group in which R is chloro.

The novel 16,17-spiro-orthoester corticoids of the present invention possess anti-inflammatory and glucocorticoid activity. Accordingly, the present compounds are useful in the treatment of allergic diseases, collagen diseases, skin diseases, and the like. In this usage, the compounds of the present invention are administered and used in the same manner as other corticoid steroid anti-inflammatory agents, such as fluocinolone acetonide.

The process of the present invention for preparing the compounds of the present invention of formulas (A) and (B) above comprises reacting the corresponding l6a,l7a-dihydroxy steroid with an O-alkyl alkanoic acid lactonium tetrafluoroborate in the presence of base.

The O-alkyl alkanoic acid lactonium tetrafluoroborate reagent is prepared by reacting together a trialkyloxonium tetrafluoroborate and an alkanoic acid lactone of four to seven carbon atoms.

In the present invention, the useful alkanoic acid lactones of four to seven carbon atoms are butyric acid lactone, pentanoic acid lactone, hexanoic acid lactone, and heptanoic acid lactone.

In the present invention, suitable trialkyloxonium tetrafluorobates include those known in the art, preferably the lower alkyl compounds, such as trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, tripropyloxonium tetrafluoroborate, and the like.

in the present invention, suitable bases include ammonia; primary alkylamines, e.g., methylamine, ethylamine, isopropylamine, n-propylamine, and the like; secondary alkyl-amines, e.g., dimethylamine, diethylamine, methylpropylamine, and the like; trialkylamines, e.g., trimethylamine, triethylamine, and the like; and monocyclic heterocyclic amines, e.g., pyridine, collidine, piperidine, morpholine, and the like.

The principal reaction hereof is conducted by reacting together a 16, l7-dihydroxy starting steroid with the O-alkyl alkanoic acid lactonium tetrafluoroborate, preferably in liquid inert organic reaction media. The reaction is conducted at temperatures ranging from about 0 to about 30 and for a period of time sufficient to complete the reaction ranging from about 5 minutes to about 1-5 hours. In the practice of this process, the reactions are contacted and maintained in any convenient order or fashion preferably within the given temperature range. After the reaction, the product is separated and isolated from the reaction mixture by any of the usual and conventional techniques such as evaporation, filtration, decantation, extraction, chromatography, and the like.

Suitable liquid inert organic reaction media in the present invention include those usually employed in organic reactions such as aromatics, e.g., benzene, toluene; ethers e.g., dioxane, diethylether, and the like; and, preferably, the halogenated hydrocarbons, e.g., chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, and the like; either individually or mixtures thereof.

The reaction consumes the reactants on the basis of one equivalent of the l6a,l7a-dihydroxy steroid per equivalent of the O-alkyl alkanoic acid lactonium tetrafluoroborate per equivalent of base. However, the relative amounts of the reactants employed are not critical, some of the desired product being prepared when employing any proportions thereof. In the preferred embodiments, from one to about five equivalents of each of the O-alkyl alkanoic acid lactonium tetrafluoroborate and base are employed per equivalent of l7a-dihydroxy starting steroid.

The O-alkyl alkanoic acid lactonium tetrafluoroborate is prepared by reacting together a trialkyloxonium tetrafluoroborate and an alkanoic acid lactone, preferably in liquid inert organic reaction media at from about to about C. and for from about 24 to 48 hours. This method is more completely described in Ber. 89, 2060 (1965), which is hereby incorporated by reference.

The process of the present invention and the process for preparing the O-alkyl alkanoic acid lactonium tetrafluoroborate are each, in the preferred embodiments, conducted under anhydrous conditions.

The process of the present invention can be practiced upon starting materials bearing the substituents defined by each of R (when other than hydroxy), R, R", R, and Z. The starting l6a,l7a-dihydroxy compounds are known and can be prepared in accordance with known procedures-see U.S. Pat. Nos. 3,048,581 and 3,053,838. If necessary, starting materials not containing a la-hydroxy group can be incubated with Streptomyces Roseochromogenus in accordance with the procedure known per se in the art. In the alternative manner, the corresponding known laJla-acetonide compounds can be cleaved with acid in accordance with the procedure known per se in the art. The l6a,l7a-acetonide starting compounds are also useful for preparing the corresponding 2l-alkoxy and phenyloxy ethers with subsequent cleavage of the l6a,l7a2l of the l6a,l7a-acetonide compounds is conducted by treating the corresponding 2l-hydroxy compounds with silver oxide and an alkyl halide or phenyl halide in an inert organic solvent at a temperature from 0C. to the reflux temperature of the reaction mixture, as set forth in U.S. patent application Ser. No. 822,049 filed May 5, 1968 now abandoned by Berkoz, Cross, Edwards, and Fried for Steroid Ethers, the discussion of this method of which application is hereby incorporated by reference.

Alternatively, the molecular substituents can be introduced after the principal reaction hereof, if more suitable from a chemical standpoint. One exception to this is the generation of the 9,1l-fluorohydrin group which is best introduced prior to the preparation of the orthoester product.

The C-2l esters can be used as a protecting group when it is desired to prepare a ZI-hydroxy final product, the ester being conventionally base hydrolyzed after the principal reaction hereof.

The following preparation and examples further illustrate the manner by which the present invention can be practiced and represent, in one aspect, the best mode for carrying out the invention. As such, however, they should be construed merely as illustrative and not as limitative upon the overall scope hereof.

PREPARATION 1 to stand overnight at room temperature to provide a solution of O-ethyl acid lactonium tetrafluoroborate.

In accordance with the foregoing procedure, the alkanoic acid lactones listed in Column A below are butyric reacted with the trialkyloxonium tetrafluoroborates listed in Column B below to provide the respective reagents listed under Column C below.

Column A Column B butyric acid trimethyioxonium lactone tetrafluoroborate pentanoic acid triethyloxonium lactone tetrafluoroborate hexanoic acid tri-n-propyloxonium lactone tetrafluoroborate heptanoic acid lactone Column C O-methyl butyric acid lactonium tetrafluoroborate O-ethyl butyric acid lactonium tetrafluoroborate O-n-propyl butyric acid lactonium tetrafluoroborate O-methyl pentanoic acid lactonium tetrafluoroborate O-ethyl pentanoic acid lactonium tetrafluoroborate O-n-propyl pentanoic acid lactonium tetrafluoroborate O-methyl hexanoic acid lactonium tetrafluoroborate O-ethyl hexanoic acid lactonium tetrafluoroborate O-n-propyl hexanoic acid hexanoic acid lactonium tetrafluoroborate O-methyl heptanoic acid lactonium tetrafluoroborate O-ethyl heptanoic acid lactonium tetrafluoroborate O-n-propyl heptanoic acid lactonium tetrafluoroborate EXAMPLE 1 6afluoro-9a,l lB-dichloro-Zl-acetoxypregna-1,4- diene-16a,l7a-diol-3,20-dione (l 15 mg.) is dispersed in 4.5 ml. of dry methylene chloride containing 50 mg. of dry triethylamine. To the resultant mixture is added 0.4 ml. of the O-ethyl butyric acid lactonium tetrafluoroborate solution prepared in Preparation 1 in a dropwise fashion and at room temperature with stirring over a period of i0 minutes. The resultant mixture is then filtered through a column of alumina and then crystallized to yield the 6a-fluoro-9a,l lB-dichloro-i 0,17a-oxolan-2,2-ylidenedioxy-2l-acetoxypregnal ,4-diene-3 ,ZO-dione.

EXAMPLE 2 6a,9a-difluoro-2 i-chloropregna-l ,4-dienel 1,6,16a,l7-triol-3,20-dione mg.) is dispersed in 10 ml. of dry methylene chloride containing 50 mg. of dry trimethylamine. To the resultant solution is then added 0.4 ml. of the O-ethylbutyric acid lactonium tetrafluoroborate solution prepared in Preparation 1 in a dropwise fashion and at room temperature with stirring over a period of 10 minutes. The resultant reaction mixture is then filtered through a column of alumina and subjected to preparative thin layer chromatography to provide the 60:,9a-difluoro-l6a,l7a-oxolan- 2',2'2 l -'chloropregna-l ,4-dienl 1 3-01- 3,20-dione.

EXAMPLE 3 6a,9a-difluoro-2 1 -acetoxypregna-l ,4-dienel1B,!6a,l7a-triol-3,20-dione (150 mg.) and l50 mg. of triethylamine are dispersed in ml. of methylene chloride at room temperature with stirring. To the resultant mixture is added 0.6 ml. of a solution of O- ethyl butyric acid lactonium tetrafluoroborate as prepared in Preparation 1 with stirring and over a period of IS minutes. After this time, the reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are subjected to preparative thin layer chromatography to provide the 6a,9a-difluoro- 1 601,1 7a-oxolan-2,2-ylidenedioxy-2 1 acetoxy-pregna-l ,4-dien-l lB-ol-3,20-dione product.

EXAMPLE 4 EXAMPLE 5 The procedure of Example 3 is repeated using, in lieu of O-ethyl butyric acid lactonium tetrafluoroborate reagent, each of O-ethyl hexanoic acid lactonium tetrafluoroborate and O-ethyl heptanoic acid lactonium tetrafluoroborate to provide 6a,9a-difluoro- 1601,] 7a2',2-ylidenedioxy-2 l -acetoxypregnal,4-dien-l lB-ol-3,20-dione and 6a,9a-difluorol6a,l 7012, 2-ylidenedioxy-2 l -acetoxypregna-l ,4-dien-l lB-ol-3,20-dione respectively.

EXAMPLE 6 To a solution of l g. of 6a,9a-difluoro-16oz,l7a-oxclan-2',2'-ylidenedioxy-2l-acetoxypregna-l,4-dien-1 1 B-ol-3,20-dione in 50 ml. of methanol is left for 3 hours with a 5 percent solution of potassium hydroxide in 10 ml. of water at 0 under nitrogen. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality and dried to yield 6a,9a-difluoro-l6a,l7a-oxolan- 2,2 l ,4-diene-l lB,2l-diol-3,20- dione which is recrystallized from methylene chloridezether.

In like manner, the foregoing hydrolysis procedure can be utilized to prepare the other l6a,l7a-spiroortho-ester products hereof containing a 2 1 -hydroxyl.

EXAMPLE 7 The procedures of Examples 1, 2, 3, and 4 are repeated utilizing, in lieu of the inert liquid organic reaction media used therein, the inert liquid organic reaction media set forth in Column D below, and, in addition, utilizing, in lieu of the amine used in these examples, those amines set forth in Column E below, with similar results in each instance.

Column D Column E carbon tetrachloride chlorornethane ethyl amine diethyl ether di-n-propyl amine dioxane isopropyl amine toluene pyridine mesitylene collidine Similarly, the foregoing modifications, when employed at a temperature of 0, affords similar results in each instance.

EXAMPLE 8 The procedures of Examples 1 and 2 are repeated employing, in lieu of O-ethyl butyric acid lactonium tetrafluoroborate, O-methyl pentanoic acid lactonium tetrafluoroborate to provide the 6a-fluoro-9a,ll/3- dichloro-l6a,l7a-oxan-2',2'-ylidenedioxy-2l-acetoxypregna-l,4-diene-3,20-dione and 6a,9a-difluoro- 1 601,1 7a2',2'-ylidenedioxy-2 l -chloropregna- 1 ,4- dien-l lB-ol-3,20-dione products, respectively.

EXAMPLES 9 to 37 In accordance with the foregoing procedures, the following products are prepared by reacting the corresponding l6a, l 7oz-dihydroxy starting steroid with the appropriate O-alkyl alkanoic acid lactonium tetrafluoroborate reagent.

l601,17a-oxolan-2,2'-ylidenedioxypregna-4-ene- 3,1 1,2l-trione,

16a, 1 7a-oxolan-2,2-ylidenedioxypregna-l ,4-

diene-l 113,2 1 -diol-3,20-dione,

16a, 1 7a-oxan-2',2-ylidenedioxypregna-l ,4-dienel lB,2l-diol-3,20-dione, l6a,l7a-oxolan-2,2-ylideneclioxy-2l-acetoxypregna-l ,4-diene-l lB-ol-3,20-dione,

1601,] 7a-oxepan-2,2'-ylidenedioxy-2 l-acetoxypregna-1,4-dien-l lfl-ol-3,20-dione, 6a,2l-difluoro-l601,17a-oxocan-2',2-ylidenedioxypregnal ,4,6-trien-l l B-ol-3,20-dione chloropregna-4,6-dien-l lB-ol-3,20-dione, 901,1lB,2l-trichloro-l6a,l7a-oxepan-2,2'-

ylidenedioxy-pregna- 1 ,4,6-triene-3 ,ZO-dione, 901,113,21-trichloro-l6a,l7a-oxepan-2',2'-

ylidenedioxy-pregnal ,4-diene-3 ,20-dione, 6q,9a-difluoro-l 601,1 7a-oxolan-2 ',2'-ylidenedioxypregna-4-en-l l/3-ol-3,20-dione, 1 601,1 7a-oxan-2,2'-ylidenedioxy-2l-methoxypregna-l ,4-dien-1 lB-ol-3,20-dione,

6oz-methyl-9a,l lB-dichloro-l6a,l7a-oxepan-2,2-

ylidenedioxy-2 l -phenyloxypregna-4,6-diene-3 ,20- dione,

6a-chloro- 1 6a, 1 7a-oxolan-2',2-ylidenedioxypregn- 4-ene-l 1,6,2 1 -diol-3,20-dione,

2 l -acetoxy-pregna-4,6-diene-3 ,20-dione,

ylidenedioxypregn-4-en-2 l -ol-3 ,20-dione,

1 601,1 7u-0xocan-2,2'-ylidenedioxy-2 l bromopregna-l ,4-dien-l l B-ol-3,20-dione, 6a-fluoro-9a,l 13,21-trichloro-16a,l7a-oxolan- 2 ,2 -ylidene-dioxypr egna-l ,4-dien-3 ,20-dione,

601,2 ldifluoro-Q a, 1 B-dichloro-l 6a, 1 7a-oxolan- 2',2-ylidenedioxy-pregna-1 ,4 dien-2l-ol-3 ZO-dione,

Formulas (A) and (B):

6a-fluoro-9a,l lB-dichloro- 1 6a, 1 7a-oxolan-2,2

ylidenedioxy-pregna-l ,4-dien-21-ol-3,20-dione, 6a-fluoro-9a.l 113,21 -trichloro-l6a,1 7a-oxan-2',2'-

yiidene-dioxypregna-l ,4-diene-3 ,20-dione, 6a,2 l -difluoro-9a, 1 1 fl-dichloro- 1 601,1 7q-oxan- 2'-ylidenedioxy-pregna-1 ,4-diene 3 ,20 dionc; r 6a-fluoro-9a,1 1B-dichloro-16a,17a-oxan-2,2'-

ylidenedioxy-pregna-l ,4-dien-2 l -ol-3,20-dione, 6,6-difluoro- 1 601,1 7a-0xo1an-2',2-ylidenedioxypregn-4-ene-3 ,l 1,20-trione, 6,6-difluoro-160:,17a-oxolan-2,2'-ylidenedioxypregna-1,4-diene-l 113,2 1-diol-3,20-dione, 6,6-difluoro-16a,!7a-oxan-2,2'-ylidenedioxypregna-l ,4-diene-i 13,2 1 -diol-3 ,ZO-dione, 6,6-difluoro-160,17a-oxolan-2,2-ylidenedioxy-2lacetoxy-pregna-l ,4-dien-l 1/3-ol-3,20-dione, 6,6-dilfuoro-l611,17a-oxepan-2',2'-ylidenedioxy-21- acetoxy-pregna-l ,4-dien-l lB-ol-3 ,20-dione, 6,6,2l-trif1uoro-16a,l7a-oxocan-2',2ylidenedioxypregna-1,4-dien-1 lp-ol-3,20-dione, and 6,6,9a,2 l-tetrafluoro- 1 6a, 1 7a-oxan-2,2'-

ylidenedioxypregn-4-ene-3,1 1,20-trione, 6a-fluoro-9a,l IB-dichloro- 1 6a, 1 7a-oxolan-2,2- ylidenedioxy-Z l-acetoxypregna-1,4-diene-3 ,20- dione, 6,6-difluoro-9a,l 1/3-dichloro-l6a,l 7a-oxolan-2',2'- ylidene-dioxy-21-acetoxypregna-1 ,4-diene-3 ,20- dione, 6,6,9a-trichloro- 1 601,1 7a-oxolan-2 ,2 -ylidenedioxy- 21 -chloropregna- 1 ,4-dien-1 lB-ol-3 ,20-dione, 6,6,9a-trifluoro- 1 6a,] 7a-oxolan-2 ,2-ylidenedioxy- 21-acetoxypregna-l,4-dien-l lB-ol-3 ,ZO-dione, 6,6-difluoro-9a,l 1 [3-dichloro-1 6a,] 7a-oxolan-2 ',2'- ylidene-dioxypregnal ,4-dien-2 l -ol-3,20-dione, 6,6-difluoro-9a,1 1B,21-trichloro l6a,l7a-oxolan-2' ,2 '-ylidene-dioxypregnal ,4-diene-3 ,20-dione, 6,6,21-trifluoro-9a,1 lB-dichloro-lfia,17a-oxo1an 2 ,2'-ylidene-dioxypregna-l ,4-diene-3,20-dione. What is claimed is: l. A compound selected from those represented by wherein, in each applicable formula,

R is hydrogen, hydroxy, fluoro, chloro, bromo, al-

koxy, phenyloxy, or carboxylic acyloxy of less than 12 carbon atoms; R is hydrogen, fluoro, chloro, bromo, or methyl; 331%. !15111989912 11? bromo; R is oxygen or the group in which R is hydroxy or, (when R is bromo or chloro bromo, chloro, or fluoro;

each Z is a carbon-carbon single bond or a carboncarbon double bond; and

n is the positive integer 1, 2, 3, or 4.

2. A compound selected from those represented by Formula A of claim 1.

3. A compound selective from those of claim 2 wherein N is the positive integer l.

4. A compound selected from those of claim 3 wherein R' i hydroxy, chloro or fluoro, R is fluoro, R is chloro, and R is the group mi. R

in which R is chloro.

5. The compound selected from those of claim 3 which is 6a-fluoro-9a,l lfi-dichloro- 1 601,1 7a-oxolan-2 ,2 '-ylidene-dioxy-2 l -acetoxypregna-l ,4-diene-3 ,20- dione.

6. The compound selected from those of claim 3 which is 6a,9a-difluoro- 1 6a, 1 7a-oxolan-2 ',2 ylidenedioxy-2 l -chloropregna- 1 ,4-dien-l 13-01-330- dione.

7. The compound selected from those of claim 3 which is 6a,9a-difluoro- 1 6a, 1 7a-oxolan-2 ,2- ylidenedioxy-2 1 -acetoxypregna-l ,4-dien-1 lB-ol-3,20- dione.

8. The compound selected from those of claim 3 which is 16a,17a-oxolan-2',2'-ylidenedioxypregna- 1,4-diene-l 16,2 1 -diol-3,20-dione.

9. The compound selected from those of claim 3 which is l6a,17a-oxolan-2',2'-ylidenedioxy-2l-acetoxypregna-l ,4-dien-1 lB-ol-3,20-dione.

10. The compound selected from those of claim 3 which is 6a-fluoro-9a,1lfl-dichloro-loaJ7a-oxolan-2 ,2 -ylidene-dioxypregna-l,4-dien-21-ol-3,20-dione.

11. The compound selected from those of claim 3 which is 6a-fluoro-9a,l113,21-trichloro-l6a,l7a-oxclan-2 ,2 -ylidenedioxypregna- 1 ,4-diene-3 ,20-dione.

12. The compound selected from those of claim 3 which is 6a,21-dif1uoro-9a,l 1fl-dichloro-16a,l7a-oxolan-2 ',2-y1idenedioxypregnal ,4-diene-3 ,ZO-dione.

13. A compound selected from those represented by Formula B of claim 1.

14. A compound selected from those represented in claim 13 wherein n is the positive integer 1.

15. The compound selected from those-of claim 14 wherein R is hydroxy, chloro, or fluoro, R is chloro, and R is the group in which R is chloro.

16. The compound selected from those of claim 14 which is 6,6-difluoro-9a,llB-dich1oro-l6a,l7a-oxwhich is 6,6-difluoro-l6a,l7a-oxolan-2,2'- ylidenedioxy-Z l-acetoxypregna-l ,4dien-l lB-ol-3,20- dione.

21. The compound selected from those of claim 14 which is 6,6-difluoro-9a,llB-dichloro-l6a,l7a-oxolan-2',2-ylidenedioxypregna-l ,4-diene-2 l -ol-3 ,20- dione.

22. The compound selected from those of claim 14 which is 6,6-difluoro-9a,l 1,8,2l-trichloro-l6a,l7a-0xclan-2 ',2'-ylidenedioxypregna-1,4-diene-3,20-dione.

23. The compound selected from those of claim 14 which is 6,6,2l-trifluoro-9a,l lB-dichloro-l 6a,17a-oxclan-2,2-ylidenedioxypregna-l ,4-diene-3 ,20-dione. 

1. A compound selected from those represented by Formulas (A) and (B):
 2. A compound selected from those represented by Formula A of claim
 1. 3. A compound selective from those of claim 2 wherein N is the positive integer
 1. 4. A compound selected from those of claim 3 wherein R1 i hydroxy, chloro or fluoro, R2 is fluoro, R3 is chloro, and R4 is the group in which R5 is chloro.
 5. The compound selected from those of claim 3 which is 6 Alpha -fluoro-9 Alpha ,11 Beta -dichloro-16 Alpha ,17 Alpha -oxolan-2'', 2''-ylidene-dioxy-21-acetoxypregna-1,4-diene-3,20-dione.
 6. The compound selected from those of claim 3 which is 6 Alpha ,9 Alpha -difluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-chloropregna-1,4-dien-11-ol-3,20-dione.
 7. The compound selected from those of claim 3 which is 6 Alpha ,9 Alpha -difluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-acetoxypregna-1,4-dien-11-ol-3,20-dione.
 8. The compound selected from those of claim 3 which is 16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxypregna-1,4-Diene-11 Beta ,21-diol-3,20-dione.
 9. The compound selected from those of claim 3 which is 16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-acetoxypregna-1,4-dien-11 Beta -ol-3,20-dione.
 10. The compound selected from those of claim 3 which is 6 Alpha -fluoro-9 Alpha ,11-dichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidene-dioxypregna-1,4-dien-21-ol-3,20-dione.
 11. The compound selected from those of claim 3 which is 6 Alpha -fluoro-9 Alpha ,11 Beta ,21-trichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxypregna-1,4-diene-3,20-dione.
 12. The compound selected from those of claim 3 which is 6 Alpha ,21-difluoro-9 Alpha ,11 Beta -dichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxypregna-1,4-diene-3,20-dione.
 13. A compound selected from those represented by Formula B of claim
 1. 14. A compound selected from those represented in claim 13 wherein n is the positive integer
 1. 15. The compound selected from those of claim 14 wherein R1 is hydroxy, chloro, or fluoro, R3 is chloro, and R4 is the group in which R5 is chloro.
 16. The compound selected from those of claim 14 which is 6,6-difluoro-9 Alpha ,11 Beta -dichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-acetoxypregna-1,4-diene-3,20-dione.
 17. The compound selected from those of claim 14 which is 6,6,9 Alpha -trifluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-chloropregna-1,4-dien-11 Beta -ol-3,20-dione.
 18. The compound selected from those of claim 14 which is 6,6,9 Alpha -trifluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-acetoxypregna-1,4-dien-11 Beta -ol-3,20-dione.
 19. The compound selected from those of claim 14 which is 6,6-difluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-pregna-1, 4-diene-11 Beta ,21-diol-3,20-dione.
 20. The compound selected from those of claim 14 which is 6,6-difluoro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxy-21-acetoxypregna-1,4-dien-11 Beta -ol-3,20-dione.
 21. The compound selected from those of claim 14 which is 6,6-difluoro-9 Alpha ,11 Beta -dichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxypregna-1,4-diene-21-ol-3,20-dione.
 22. The compound selected from those of claim 14 which is 6,6-difluoro-9 Alpha ,11 Beta ,21-trichloro-16 Alpha ,17 Alpha -oxolan-2'',2''-ylidenedioxypregna-1,4-diene-3,20-dione. 